PROJECT SUMMARY Improve PAD PERformance with METformin: The PERMET Trial. Our work and that of others has established that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and increased rates of mobility loss compared to people without PAD. However, few therapies are available that improve functioning or prevent functional decline in people with PAD. Metformin is an inexpensive, widely available, well tolerated biguanide medication and the most commonly prescribed drug for Type 2 diabetes mellitus worldwide. Recent pre-clinical and preliminary human evidence suggest that metformin has previously unrecognized therapeutic properties. Therapeutic properties of metformin in pre-clinical models that may benefit people with PAD include: calf skeletal muscle increases in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) (a major regulator of mitochondrial biogenesis), calf skeletal muscle increases in mitochondrial protein expression and activity, increases in capillary density in ischemic tissue, reductions in oxidative stress, increased autophagy (repair of cellular damage), and improved endothelial function. These therapeutic properties target pathophysiologic conditions present in PAD. Therefore, we hypothesize that metformin will improve lower extremity functioning in people with PAD, by facilitating favorable changes in calf skeletal muscle and by increasing calf skeletal muscle perfusion. No randomized clinical trials have studied whether metformin improves lower extremity functioning in PAD. A definitive trial is needed. We propose a placebo controlled double-blind randomized clinical trial to establish whether metformin (2,000 mgs daily) improves and/or prevents decline in walking performance in people with PAD. Participants will be 212 people with PAD who do not have diabetes mellitus, since metformin is a first-line therapy for Type 2 diabetes. Our primary outcome is change in six-minute walk at 6-month follow-up. Secondary outcomes are 6-month changes in treadmill walking performance, brachial artery flow-mediated dilation, calf skeletal muscle biopsy measures, patient-reported walking performance, and quality of life. Calf muscle outcomes consist of changes in PGC-1? abundance, mitochondrial quantity, mitochondrial enzyme activity, capillary density, reactive oxygen species (ROS)-induced tissue damage, and autophagy. If metformin improves functional performance and prevents functional decline in PAD, this widely available, inexpensive, and well tolerated medication will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people with PAD.